{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:52:33Z","timestamp":1791222753400,"version":"4.1.0"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    The integrity of the blood\u2013brain barrier (BBB) is crucial for maintaining the function and homeostasis of the central nervous system (CNS), with astrocytes playing a key role in this process. Our study found that infection with the Japanese encephalitis virus (JEV) promoted the translocation of high-mobility group box 1 (HMGB1) from the nucleus to the extracellular space of astrocytes, a process directly associated with BBB disruption. Through bioinformatics analysis, we identified potential targets of encephalitis and constructed a protein\u2013protein interaction (PPI) network. Subsequent functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, highlighted the calcium signaling pathway as an important regulatory mechanism. Evidence from our\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    model experiments showed that HMGB1 can induce the increase of calcium ions (Ca\u00b2\n                    <jats:sup>+<\/jats:sup>\n                    ) in astrocytes, thereby activating the calcium signaling pathway and promoting the translocation of aquaporin-4 (AQP4) to the plasma membrane, ultimately leading to BBB disruption. We also performed molecular docking and molecular dynamics simulations to determine the binding affinity between trifluoperazine (TFP) and calmodulin (CaM). TFP binds to CaM and blocks the translocation of AQP4 to the plasma membrane, thereby alleviating HMGB1-mediated BBB disruption. Overall, our data indicate that TFP protects BBB integrity through the CaM\u2013CaMKII\u2013AQP4 axis and identifies this pathway as a promising therapeutic target for the clinical treatment of Japanese encephalitis and other central nervous system diseases.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1852083","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T04:34:03Z","timestamp":1782189243000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Astrocyte-derived HMGB1 compromises the integrity of the blood-brain barrier through the CaM\/CaMKII\/AQP4 pathway and the protective function of trifluoperazine"],"prefix":"10.3389","volume":"17","author":[{"given":"Song-Song","family":"Zou","sequence":"first","affiliation":[{"name":"Key Laboratory of Exploitation and Study of Distinctive Plants of Sichuan Provincial Education Department, Sichuan University of Arts and 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